Our objective is to study the immunopathology of the X-linked recessive lymphoproliferative syndrome (XLP) which is expressed phenotypically as diverse lymphoproliferative disorders: acquired agammaglobulinemia, fatal infectious mononucleosis, or malignant lymphoma. Three comprehensive approaches are proposed: (1) Develop a registry to ascertain the prevalence, delineate phenotypic expressions, and develop diagnostic criteria. Cases will be ascertained by referrals and review of medical literature and cases in tumor registries and in pediatric and general hospitals. (2) Patients with the XLP will be evaluated for general immunocompetence using clinical, hematopathological and immunological and virological techniques. Blood, bone marrow, biopsy and autopsy specimens will be studied intensively using the above techniques. Males with XLP are probably immunodeficient to Epstein-Barr virus (EBV) and hence, we will test our hypothesis by demonstrating: a) spontaneous outgrowth of EBV-infected B cells in vitro; b) EBV shedding in saliva; c) failure to develop antibody to EBV; and d) abnormal autologous T cell responses to B cells infected by EBV in vitro. Testing is important diagnostically and could identify the immunopathogenetic mechanisms of the XLP. (3) Genetic screening for affected males with XLP and female carriers is being done by studying the Xga blood group and oculocutaneous markers, measuring general and EBV-specific immunocompetence, and detecting abnormal lymphocytes with heteroantisera raised to lymphocytes of patients and HLA-matched female siblings. Karyotyping of lymphoblastoid cell lines of patients will determine whether chromosomal breakage and marker chromosomes occur following infection by EBV in males with XLP. The development of a repository of their frozen sera, saliva and cultured lymphoblastoid cells for future studies is another objective of our study.